title: Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs.
abstract: Small-molecule multi-targeted cyclin-dependent kinase (CDK) inhibitors (CDKIs) are of particular interest due to their potent antitumor activity independent of p53 gene alterations. P53 deletion is associated with a very poor prognosis in multiple myeloma (MM). In this regard, we tested the anti-MM activity of RGB-286638, an indenopyrazole-derived CDKI with Ki-nanomolar activity against transcriptional CDKs. We examined RGB-286638's mode-of-action in MM cell lines with wild-type (wt)-p53 and those expressing mutant p53. RGB-286638 treatment resulted in MM cytotoxicity in vitro associated with inhibition of MM tumor growth and prolonged survival in vivo. RGB-286638 displayed caspase-dependent apoptosis in both wt-p53 and mutant-p53 cells that was closely associated with the downregulation of RNA polymerase II phosphorylation and inhibition of transcription. RGB-286638 triggered p53 accumulation via nucleolar stress and loss of Mdm2, accompanied by induction of p53 DNA-binding activity. In addition, RGB-286638 mediated p53-independent activity, which was confirmed by cytotoxicity in p53-knockdown and p53-mutant cells. We also demonstrated downregulation of oncogenic miR-19, miR-92a-1 and miR-21. Our data provide the rationale for the development of transcriptional CDKIs as therapeutic agents, which activate p53 in competent cells, while circumventing p53 deficiency through alternative p53-independent cell death mechanisms in p53-mutant/deleted cells.
authors.affiliation: 1] MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA [2] Leebow Institute of Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Cirstea
authors.forename: T
authors.initials: T
authors.lastname: Hideshima
authors.forename: L
authors.initials: L
authors.lastname: Santo
authors.forename: H
authors.initials: H
authors.lastname: Eda
authors.forename: Y
authors.initials: Y
authors.lastname: Mishima
authors.forename: N
authors.initials: N
authors.lastname: Nemani
authors.forename: Y
authors.initials: Y
authors.lastname: Hu
authors.forename: N
authors.initials: N
authors.lastname: Mimura
authors.forename: F
authors.initials: F
authors.lastname: Cottini
authors.forename: G
authors.initials: G
authors.lastname: Gorgun
authors.forename: H
authors.initials: H
authors.lastname: Ohguchi
authors.forename: R
authors.initials: R
authors.lastname: Suzuki
authors.forename: H
authors.initials: H
authors.lastname: Loferer
authors.forename: N C
authors.initials: NC
authors.lastname: Munshi
authors.forename: K C
authors.initials: KC
authors.lastname: Anderson
authors.forename: N
authors.initials: N
authors.lastname: Raje
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D009101:Multiple Myeloma / Q000473:pathology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C546217:RGB 286638; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014508:Urea; D018844:Cyclin-Dependent Kinases